Roles of tumor necrosis factor-α and interleukin-6 in regulating bone cancer pain via TRPA1 signal pathway and beneficial effects of inhibition of neuro-inflammation and TRPA1

Abstract

Background Pain is one of the most common and distressing symptoms suffered by patients with progression of bone cancer; however, the mechanisms responsible for hyperalgesia are not well understood. The purpose of our current study was to determine contributions of the sensory signaling pathways of inflammatory tumor necrosis factor-α and interleukin-6 and downstream transient receptor potential ankyrin 1 (TRPA1) to neuropathic pain induced by bone cancer. We further determined whether influencing these pathways can improve bone cancer pain. Methods Breast sarcocarcinoma Walker 256 cells were implanted into the tibia bone cavity of rats to induce mechanical and thermal hyperalgesia. ELISA and western blot analysis were used to examine (1) the levels of tumor necrosis factor-α and interleukin-6 in dorsal root ganglion and (2) protein expression of tumor necrosis factor-α and interleukin-6 receptors (TNFR1 and IL-6R) and TRPA1 as well as intracellular signals (p38-MAPK and JNK). Results Tumor necrosis factor-α and interleukin-6 were elevated in the dorsal root ganglion of bone cancer rats, and expression of TNFR1, IL-6R, and TRPA1 was upregulated. In addition, inhibition of TNFR1 and IL-6R alleviated mechanical and thermal hyperalgesia in bone cancer rats, accompanied with downregulated TRPA1 and p38-MAPK and JNK. Conclusions We revealed specific signaling pathways leading to neuropathic pain during the development of bone cancer, including tumor necrosis factor-α-TRPA1 and interleukin-6-TRPA1 signal pathways. Overall, our data suggest that blocking these signals is beneficial to alleviate bone cancer pain.

Antinociceptive effect of intrathecal injection of miR-9-5p modified mouse bone marrow mesenchymal stem cells on a mouse model of bone cancer pain

“…The pathophysiological changes in the central nervous system of the mouse model with bone cancer pain have been well studied [20]. The increase of cytokines is the consistent findings over the last decades that is believed to be the culprit leading to the persistent and resistant pain in pain sensation [21,22]. Consistent with previous studies, as shown in Fig.…”

Investigating the Multitarget Mechanism of Traditional Chinese Medicine Prescription for Cancer-Related Pain by Using Network Pharmacology and Molecular Docking Approach

“…TNF mainly encoded a multifunctional proinflammatory cytokine, combination with the transient receptor potential vanilloid-1 (TRPV1), playing an important role in inflammatory pain and nerve pain [ 26 , 27 ]. Downregulating TNF expression can effectively inhibit the occurrence of inflammatory pain and nerve pain [ 28 ]. Moreover, MAPK8, JUN, AKT1, and RELA can regulate cell proliferation and cell cycle, which was crucial in tumorigenesis.…”

Clinical prognostic factors in advanced epithelioid haemangioendothelioma: a retrospective case series analysis within the Italian Rare Cancers Network

“…Systemic inflammation and chemokine mediators' cascade have been implicated in pain pathophysiology both in cancer patients and in experimental cancer pain models. 22 , 23 , 24 , 25 , 26 , 27 Given the importance of the pain course in this disease we advocate that future prospective series should receive formal pain assessment.…”